QP 
141 
H6 


COLUMBIA  UNIVERSITY  PRESS 
SALES  AGENTS 

NEW  YORK: 

LEMCKE  &  BUECHNER 

30-32   EAST  2Orn  STREET 

LONDON: 

HUMPHREY  MILFORD 
AMEN  CORNER,  E-C. 

SHANGHAI: 

EDWARD  EVANS  &  SONS,  LTD. 
30  NORTH  SZECHUEN  ROAD 


NEWER  ASPECTS  OF  THE 
NUTRITION  PROBLEM 


BY 
F.  GOWLAND  HOPKINS 

Professor  of  Biological  Chemistry 
University  of  Cambridge,  England. 


IFlew 

COLUMBIA  UNIVERSITY  PRESS 
1922 

All  rights  reserved 


COPYRIGHT,  1922 
By  COLUMBIA  UNIVERSITY  PRESS 


Printed  from  type,  January  1922 


PROFESSOR  FREDERICK  GOWLAND  HOPKINS 


Introductory  Remarks 

By  George  B.  Pegram 

COLUMBIA  UNIVERSITY,  NEW  YORK,  N.  Y. 

It  is  our  pleasure  to  be  assembled  this  evening  to  hear  as 
the  Chandler  Lecturer  for  the  present  year  a  gentleman  who  is 
widely  known  among  chemists  as  a  pioneer  in  the  very  remarkable 
developments  of  our  knowledge  that  have  been  brought  about 
through  the  study  of  food  accessories  such  as  vitamines. 

I  have  the  honor  of  introducing  Professor  Frederick  Gowland 
Hopkins,  of  Cambridge  University,  England. 


Medal  Address 

Newer  Aspects  of  the  Nutrition  Problem 
By  F.  Gowland  Hopkins 

PROFESSOR  OF  BIOLOGICAL  CHEMISTRY,  UNIVERSITY  OF  CAMBRIDGE,  CAM- 
BRIDGE, ENGLAND 

NUTRITIONAL  STUDIES  AS  A  BRANCH  OP  APPUED  CHEMISTRY 
The  study  of  nutrition  is  most  productive  when  it  is  followed 
as  a  branch  of  applied  organic  chemistry.  As  such  it  doubtless 
suffers  certain  disadvantages.  It  calls  for  workers  fully  ac- 
quainted with  the  technic  of  the  chemical  laboratory  and  pos- 
sessed of  all  that  is  special  in  the  chemist's  mental  equipment 
and  mode  of  thought.  Yet  it  calls  for  the  application  of  these 
possessions  in  a  region  which  is  perhaps  more  remote  from  the 
chemist's  experiences  during  his  training  than  are  any  other  of  the 
many  regions  in  which  his  science  is  applied.  The  successful 
pursuit  of  biochemistry,  of  which  science  nutritional  studies 
form  a  part,  calls  for  a  second  discipline.  The  young  chemist 
having  received  his  primary  training  must  be  content  to  become 
next  something  of  a  biologist;  he  must  know  enough  about 
animals  and  plants  to  appraise  the  problems  which  their  or- 
ganization presents;  he  must  acquire  a  biological  outlook. 
Chemistry  is  a  basal  science  underlying  the  practice  of  so 
many  human  activities  that  a  large  proportion  of  those  who 
start  with  a  chemical  training  must  ultimately  add  to  their 
equipment  other  kinds  of  expert  knowledge  before  qualifying 
for  their  life's  work.  It  is  a  pity  that  so  few  up  to  now  have 
chosen  biological  qualifications.  Hitherto,  the  primary  train- 
ing of  most  of  those  who  have  investigated  biochemical  problems 
has  been  biological  or  medical.  Such  workers  have  done  very 
well,  but  as  knowledge  progresses  it  becomes  more  and  more 
necessary  that  at  least  some  of  the  work  should  be  done  by  those 
whose  chemical  knowledge  is  primary  and  not  secondary. 

(7) 


But  I  have  referred  to  certain  disadvantages  suffered  by 
biochemistry  and  you  will  think  of  one  of  them.  It  has  hitherto 
been  difficult  to  point  clearly  to  a  professional  (as  distinct  from 
an  academic)  career  for  the  young  man  who  thinks  of  devoting 
himself  to  the  subject.  Only  in  connection  with  medicine  has 
it  hitherto  offered  professional  opportunities,  and  medical 
qualification  is  often  first  demanded  of  its  votaries.  This 
state  of  affairs  is  rapidly  altering.  Medical  practice  can  and  will 
in  the  future  be  helped  by  workers  whose  training  has  comprised 
something  less  than  a  complete  medical  course.  Biochemical 
knowledge,  moreover,  is  being  sought  in  many  unexpected 
quarters.  The  scientific  representatives  of  a  firm  that  manu- 
factures explosives  on  a  great  scale  asked  me  some  time  ago 
to  supply  them  with  a  biochemist.  At  first  it  seemed  difficult 
to  know  why;  but  the  explanation  was  simple  enough.  There 
is,  or  was,  some  anxiety  about  the  supply  of  glycerol.  Fats 
which  used  to  be  hydrolyzed  are  now  being  used  intact  in  all 
sorts  of  fresh  ways,  and  there  is  less  glycerol  as  a  by-product. 
Hence  a  desire  to  develop  the  methods  by  which  it  is  produced  by 
microorganisms,  and  the  biochemist  gets  an  opportunity.  This 
is  but  one  illustration.  I  can  say  with  certainty  that,  in  Great 
Britain  at  any  rate,  there  is  a  demand  for  professional  biochem- 
ists which  is  greatly  in  excess  of  the  present  supply.  This  I 
find  satisfactory,  for  if  a  profession  opens  up  we  shall  find  it 
easier  to  obtain  workers  who  during  one  period  at  least  of  their 
career  will  help  advance  the  science  itself. 

NEED  FOR  ORGANIC  CHEMISTS  IN  BIOLOGY 

I  find  it  difficult,  when  addressing  an  audience  composed 
largely  of  chemists,  to  avoid  a  propagandist  attitude :  because 
it  is  so  very  desirable  that  a  proportion  of  our  young  chemists, 
greater  than  heretofore,  should  devote  themselves  to  biological 
problems.  I  will  confess  that  I  am  at  the  moment  thinking  in 
particular  of  organic  chemistry.  For  it  seems  to  me.  that  on 
the  whole  the  tendency  has  been  for  those  who  have  especially 
qualified  as  physical  chemists  to  devote  themselves  to  biology 
rather  than  their  colleagues  who  are  more  particularly  accustomed 
to  think  in  terms  of  molecular  structure.  Now  no  student  of 
the  plant  or  the  animal  can  do  otherwise  than  offer  a  hearty 
welcome  to  the  physical  chemist.  He  is  now  providing  knowledge 
for  which  a  whole  generation  of  biological  workers  has  been 
waiting.  But  if  it  be  supposed  that  the  application  of  the  meth- 
ods of  physical  chemistry,  elegant  and  precise  as  they  are,  or 
the  physical  chemist's  particular  way  of  looking  at  things,  is 
going  to  take  us  more  directly  and  quickly  into  the  secret  habi- 
tation of  life  than  other  forms  of  chemical  study;  in  particular 
if  it  be  supposed  that  considerations  of  molecular  structure  are 
not  essential  to  an  understanding  of  living  processes — then, 
I  am  sure,  such  suppositions  are  wrong. 

In  the  main,  though  not  of  course  exclusively,  the  physical 
(8) 


chemist  in  biology  is  engaged  in  a  study  of  the  colloidal  appara- 
tus in  which  the  dynamic  events  of  life  occur  and  in  carefully 
and  precisely  defining  a  group  of  circumstances  which  conditions 
those  events.  We  could,  however,  picture  a  physical  system, 
composed  of  colloids  similar  to  those  which  exist  in  the  living 
cell,  endowed  with  a  characteristic  structure,  and  in  contact 
with  electrolytes  at  a  particular  hydrogen-ion  concentration, 
which  would  closely  resemble  a  living  unit  when  viewed  from  a 
purely  statical  standpoint;  but  unless  what  is  ordinarily  called 
metabolism  occurs  in  such  a  system  it  is  dead.  Now  metabo- 
lism consists  in  the  continuous  process  of  a  set  of  organic  chem- 
ical reactions  in  dynamic  adjustment.  Until  our  knowledge 
of  these  reactions  and  of  their  mutual  relations  is  complete, 
our  knowledge  of  living  tissues  will  remain  incomplete.  This 
knowledge  cannot  come  without  continued  thought  and  experi- 
ment on  the  lines  of  what  we  are  accustomed  to  call  organic 
chemistry.  This  applies  to  biochemistry  as  a  whole,  and  not 
least  to  that  branch  of  it  which  comprises  the  study  of  nutrition. 
There  is  of  course  one  method  of  estimating  the  nutritional 
needs  of  the  body  which  avoids  consideration  of  chemical  de- 
tails. They  may  be  dealt  with  from  the  standpoint  of  ener- 
getics. Indeed,  as  the  last  century  closed,  the  facts  of  nutrition 
were  coming  to  be  viewed  more  and  more  exclusively  from  this 
standpoint.  The  criterion  of  an  efficient  dietary  was  apparently 
destined  to  be  its  caloric  value,  and,  with  one  qualification, 
which  seemed  then  to  be  lessening  in  significance,  its  caloric 
value  alone.  The  chemical  standpoint,  in  so  far  as  it  envisaged 
detail?,  seemed  to  be  losing  its  practical  importance. 

SUCCESSES  AND  LIMITATIONS  OF  CALORIMETRY 

Those  years  saw  a  remarkable  development  in  the  technic 
of  human  calorimetry.  The  accuracy  with  which  the  energy  ex- 
changes in  the  body  came  to  be  measured  gave  rise  in  the  minds 
of  all  students  of  nutrition  to  a  sense  of  real  accomplishment 
and  to  a  feeling  that,  in  addition  to  certain  theoretical  con- 
clusions of  great  interest,  calorimetry  was  making  available, 
perhaps  for  the  first  time,  information  of  a  really  quantitative 
kind  to  serve  in  practical  guidance.  The  vague  standards 
based  upon  statistical  studies  of  the  habits  of  the  communities 
could  at  last,  it  was  felt,  be  checked,  and  if  need  be  cor- 
rected, by  data  which  were  in  the  truest  sense  scientific.  What, 
in  terms  of  energy,  are  the  basal  requirements  of  the  body?' 
What  the  caloric  equivalent  of  various  forms  of  mechanical, 
work?  What  the  efficiency  of  the  human  body  as  a  machine?1 
What  the  relative  value  of  foodstuffs  as  sources  of  muscular 
energy?  All  these  and  kindred  questions  were  being  answered 
or  the  methods  for  their  future  solution  made  clear  as  the  last 
century  closed.  They  are,  indeed,  still  being  investigated, 
and  with  increasing  accuracy,  chiefly  in  the  country  where 
they  were  first  seriously  dealt  with.  For  American  workers 

(9) 


Graham  L/usk,  Benedict,  Dubois  and  others  are  continuing  the 
work  of  Atwater  and  Rosa,  and  are  obtaining  quantitative  data 
which  can  be  so  controlled  as  to  carry  their  own  inher- 
ent proof  of  striking  and  even  startling  accuracy.  The  inves- 
tigations are  extending  into  the  domain  of  pathological  metab- 
olism, and  there  I  am  convinced  will  have  important 
bearings.  Calorimetry  as  applied  to  human  beings  is  an 
American  science,  and  this  country  should  feel  the  utmost 
pride  in  what  it  has  accomplished.  It  is,  in  fact,  impos- 
sible to  overestimate  the  theoretical  and  practical  importance 
of  the  data  of  human  calorimetry.  My  only  contention  is 
that  they  are,  and  must  always  remain,  insufficient  for 
complete  knowledge.  In  a  limited  sense  calorimetry  applies 
the  methods  of  thermodynamics  to  the  study  of  the  body  and 
its  results  share  the  advantage  of  conclusions  reached  by  these 
methods  in  other  branches  of  science.  They  involve  quanti- 
tative statements  which  will  remain  true  however  our  view  may 
change  with  regard  to  the  mechanism  underlying  those  manifes- 
tations of  change  which  permit  easy  measurement.  The  thermo- 
dynamic  method  is  however  sometimes  like  a  blind  man's  stick. 
It  carries  us  safely  along  a  path  which  we  cannot  see,  but  fails 
to  show  us  how  we  may  best  reach  our  ultimate  goal.  When 
there  is  complexity  of  a  kind  which  cannot  be  reduced  to  sta- 
tistics, the  method  of  thermodynamics  is  apt  to  fail  us.  The 
human  body  obeys  the  laws  of  thermodynamics  when,  for  this 
or  that  good  reason,  it  is  surely  perishing! 

Without,  therefore,  underestimating  for  one  moment  the  value 
of  thermal  studies  as  applied  to  nutrition,  I  think  it  must  be  ad- 
mitted that  they  in  themselves  can  never  constitute  a  sufficient 
guide  for  the  progress  of  knowledge. 

IMPORTANCE  OF  STRUCTURAL  CHEMISTRY 

Anyone,  at  any  rate,  who  will  trouble  himself  to  appraise  the 
nature  of  the  progress .  which  the  detailed  studies  of  the  last 
twenty  years  have  contributed  to  our  views  concerning  animal 
and  human  nutrition  will  not  doubt  what  I  have  said  earlier  as  to 
the  importance  of  thinking  in  terms  of  organic  chemistry.  Up 
to  the  end  of  the  last  century,  thought  about  the  chemistry  of 
living  beings  scarcely  employed  considerations  of  molecular 
structure,  or  employed  them,  at  any  rate,  in  a  very  limited 
sense.  Now,  as  the  result  of  twenty  years'  progress,  all  con- 
cerned are  doing  their  best  to  think  in  terms  of  structural  chem- 
istry; with  the  result  that  vague  views  about  metabolism  are 
giving  place  to  clearer  conceptions  from  which  must  follow  a 
better  understanding  of  the  nutritive  needs  of  the  body. 

Perhaps  only  those,  who,  like  myself,  have  had  to  talk  to 
students  about  such  matters  for  five-and-twenty  years,  can  fully 
realize  how  much  the  clarification  of  thought  has  progressed. 
MODERN  CONCEPTIONS  OF  PROTEIN  METABOLISM 

Especially,  of  course,  is  all  this  true  in  connection  with  the 
(10) 


nutritive  functions  of  protein.  So  long  as  we  had  to  fit  into 
our  mental  picture  of  what  occurs  in  living  tissues  the  hypo- 
thetical behavior  of  a  complex  molecule  of  which  we  knew  lit- 
tle, and  conceived  of  it  as  being  oxidized,  or  otherwise  utilized 
as  a  complex  whole;  oppressed  therefore  by  the  feeling  that  its 
very  complexity  would  remove  the  processes  involved  from  the 
domain  of  clear  chemical  presentation;  so  long  as  all  this  was 
the  case  we  had  to  think  in  intellectual  blinkers  about  the  func- 
tions of  protein.  But  simultaneously  with  the  beginning  of 
the  present  century,  progressive  work  began  which  has  changed 
the  outlook.  We  have  come  to  know  that  the  complex  mole- 
cule is  built  up  of  some  twenty  structural  units,  each  a  chemical 
species,  but  all  belonging  to  the  same  chemical  genus.  We 
know  the  structure  of  each  of  these  amino  acids  and  realize 
that  among  them  unity  of  type  is  combined  with  great  di- 
versity in  structural  detail,  the  unity  and  diversity  being  equally 
significant  for  the  student  of  nutrition.  We  know,  more- 
over, that  the  process  by  which  we  liberate  these  constituents 
from  the  protein  complex  in  the  laboratory — the  process  of 
hydrolysis — is  identical  with  that  which  occurs  in  digestion. 
We  know  finally  that  in  the  alimentary  canal  this  process  is 
very  completely  carried  out  before  adsorption  of  material  occurs ; 
so  that  the  immediate  phenomena  of  nutrition  begin  not  with  a 
supply  of  protein  as  such,  but  with  a  supply  of  amino  acids. 
When  we  eat  protein  we  consume,  in  effect,  not  one  substance 
but  twenty,  and  each  of  these  may  have  quite  special  functions 
in  nutrition.  All-important  to  present  and  future  progress 
is  the  fact  that  they  are  substances  of  known  molecular  structure. 
It  is  impossible,  of  course,  for  me  to  deal  historically  with  this 
advance  in  knowledge.  I  have  been  instructed  to  narrate  per- 
sonal experiences,  and  though  it  may  be  unfair  to  others  I  will 
confine  myself  to  illustrations  drawn  from  such  experiences. 
I  can  claim  that  some  eighteen  years  ago  my  imagination 
(doubtless  like  that  of  many  others)  was  greatly  stirred  by  the 
facts  then  becoming  available.  It  seemed  to  me  essential  for 
the  understanding  of  protein  nutrition,  and  for  the  analysis 
of  the  factors  concerned  in  the  maintenance  of  nitrogenous 
equilibrium,  that  the  relative  nutritive  importance  and  ulti- 
mately the  precise  fate  of  each  individual  amino  acid  should  be 
determined  separately.  In  1906,  in  conjunction  with  Miss 
Edith  Willcox  (now  Mrs.  Stanley  Gardiner),  I  published  results 
of  some  experiments  which  illustrated  the  special  nutritive  im- 
portance of  the  indole  nucleus  contained  in  tryptophan,  an 
amino  acid  first  separated  from  protein  a  few  years  earlier  by 
S.  W.  Cole  and  myself. "  Incidentally  these  experiments  in- 
dicated that  an  amino  acid  may  be  used,  not  alone  for  the  build- 
ing up  of  tissue  proteins,  but  also  immediately  and  directly  for 
more  specific  purposes.  It  is  important  when  approaching 
studies  of  metabolism  and  nutrition  to  realize  in  advance  that 
more  than  one  path  of  change  may  lie  before  any  particular  unit 

(11) 


in  the  food  eaten.  The  results  of  the  unambitious  pioneer  re 
search  just  mentioned,  in  so  far  as  it  bore  upon  the  importance 
of  the  indole  nucleus,  have  since  been  confirmed  by  myself, 
and  abundantly  by  others,  on  more  conclusive  lines.  The  fact 
recently  demonstrated  by  Kendall,  at  Rochester,  Minnesota, 
that  the  all-important  active  principle  of  the  thyroid  gland  is 
an  iodine  derivative  of  indole  has  shown  us  one  probable  reason 
for  the  importance  of  a  supply  of  tryptophan  in  the  diet.  This 
is  only  an  illustrative  instance  of  the  special  functions  which 
may  be  subserved  by  individual  parts  of  the  protein  molecule. 

The  circumstance  that  an  animal  can  be  normally  nourished 
when,  instead  of  intact  protein,  it  receives  a  complete  mixture 
of  amino  acids  has  greatly  assisted  studies  meant  to  determine 
the  relative  nutritive  importance  of  the  different  molecular 
groups, irr  the  protein  molecule.  The  original  amino  acid  mix- 
ture obtained  by  digesting  any  normal  protein  may  be  frac- 
tionated, and  this  or  that  constituent  may  be  withdrawn  from 
the  mixture  before  it  is  supplied  to  the  animal.  Ultimately, 
by  so  withdrawing  a  particular  unit  and  observing  the  effects  of 
its  withdrawal,  we  may  not  only  measure  its  importance  but 
also  obtain  information  as  to  any  special  functions  it  may  sub- 
serve. 

I  have  myself  tried  the  effects  of  withdrawing  certain  amino 
acids  besides  trytophan.  If  for  instance  an  animal  be  given 
as  its  sole  nitrogenous  nutriment,  the  amino  acid  mixture  de- 
prived of  hystidine  and  arginine,  nutrition  fails.  It  promptly 
becomes  normal  again  when  these  two  units  are  restored  to  the 
food.  The  first  of  these  substances  contains  the  iminazole 
ring,  and  the  second  gets  its  special  stamp  from  the  existence  of 
the  guanidine  group  in  its  molecule.  Now  it  is  remarkable 
that,  though  the  absence  of  both  these  amino  acids  from  the 
food  supply  is  fatal,  the  absence  of  either  alone  is  well  borne  by 
the  animal,  and  experiment  shows  that  one  can  take  the  place 
of  the  other  in  metabolism.  Considerations  of  molecular  struc- 
ture make  it  easy  to  understand  why  this  may  well  be  the  case 
and  the  body  in  this  case  clearly  takes  advantage  of  certain 
possibilities  which  are  obvious  to  the  chemist! 

CH— N  CH2N— H 


CN—  H  CH2  HN 

I  I 

CH2  CH2 

I  | 

CHNH2  CHNH2 

I  I 

COOH  COOH 

Histidine  '    Arginine 


Similarly  a  deficiency  of  tyrosine  may  be  compensated  by  a 

(12) 


larger  supply  of  the  closely  related  phenylalanine;  and  there 
are  probably  similar  cases.  Such  facts  help  to  throw  light 
upon  the  equipment  of  the  tissues  as  laboratories:  they  must 
also  be  borne  in  mind  when  we  are  estimating  the  nutritive  value 
of  any  particular  form  of  protein. 

Considerations  of  molecular  structure  made  it  probable  that 
arginine  and  histidine  might  well  be  the  precursors  of  the  purine 
bases  which  are  characteristic  constituents  of  the  nucleic  acids 
found  in  all  tissue  cells.  Led  by  the  structional  suggestions, 
Ackroyd  and  the  writer  some  years  ago  tested  this  matter  by 
feeding  experiments,  and  obtained  evidence  to  show  that  the 
suggestions  were  fulfilled.  Arginine  and  histidine  seem  to  be 
the  special  raw  material  for  the  synthesis  of  purines  in  the  body. 

On  the  other  hand,  there  are  constituent  groups  in  protein 
which  are  certainly  of  much  less  nutritive  importance  than  those 
discussed.  Especially  would  this  seem  to  be  true  of  those 
amino  acids  which  have  a  relatively  simple  constitution— the 
aliphatic  substances,  for  instance,  with  a  normal  chain  of  carbon 
atoms.  I  have  myself  found,  for  instance,  that  if  glutamic  acid, 
aspartic  acids,  and  hydroxyglutamic  acid  recently  identified  by 
Dakin  be  all  removed  from  the  amino-acid  mixture,  animals 
can  maintain  themselves  quite  well  upon  the  residual  amino 
acids.  The  contrast  between  the  fatal  effects  of  removing 
tryptophan,  which  constitutes  some  two  per  cent  only  of  a 
normal  protein,  with  the  almost  negligible  effects  of  removing  the 
amino  acids  just  mentioned,  which  may  represent  perhaps 
thirty  per  cent  of  the  protein,  is  sufficiently  striking.  There  is 
little  doubt  that  the  difference  is  due,  not  to  the  fact  that  the 
tissues  can  dispense  with  any  protein  constituent  necessary  to 
their  normal  chemical  make-up,  but  rather  to  the  range  of  synthetic 
possibilities  within  the  body.  When  deprived  of  a  supply  of 
certain  amino  acids,  it  can  synthesize  them  for  itself;  the  syn- 
thesis of  others  is  not  within  its  powers. 

Very  interesting  is  the  knowledge,  incomplete  as  yet,  which 
we  possess  concerning  the  chemical  changes  which  individual 
amino  acids  actually  undergo  in  the  body.  The  fate  of  each  is 
individual  because  its  molecular  structure  is  individual.  I 
could  indeed  better  illustrate  the  truth  of  my  opening  conten- 
tion concerning  the  importance  of  structural  considerations  in 
biological  chemistry  if  we  were  considering  intermediary  metab- 
olism rather  than  nutrition  in  the  more  limited  sense.  The 
few  facts  I  have  put  before  you  will,  however,  illustrate  it  suffi- 
ciently. 

The  outcome  of  the  recent  advances  in  knowledge  concerning 
the  chemistry  and  metabolism  of  protein  when  viewed  from  the 
standpoint  of  practical  dietetics  is  in  the  main  this:  We  cannot 
any  longer  be  content  to  speak  of  the  body's  demands  for  "protein" 
in  unqualified  terms.  The  balance  of  individual  amino  acids, 
the  relative  amount  of  this  or  that  acid,  may  be,  we  know,  very 
different  in  different  proteins,  and  this  difference  may  markedly 

(13) 


affect  the  relative  nutritive  value.     For  the  future  we  must  in 
this  connection  think  of  quality  as  well  as  quantity. 

What  we  know  about  the  functions  and  fate  of  the  other 
basal  foodstuffs,  the  carbohydrates  and  fats,  illustrates  equally 
well  the  importance  of  structural  considerations  in  biochemistry. 
But  with  these  I  cannot  deal. 

VITAMINES 

I  will  rather  pass  at  once  to  a  newer  aspect  of  our  knowledge 
concerning  the  nutritional  demands  of  the  body,  and  remind 
you  of  facts  which  more  than  any  others  illustrate  the  necessity, 
when  we  are  seeking  to  define  an  efficient  dietary,  of  consider- 
ing the  nature  of  the  material,  as  well  as  the  energy  supply.  I 
mean,  of  course,  the  facts  concerning  the  accessory  food  sub- 
stances, as  I  once  ventured  to  name  them,  or  (to  use  the  more 
familiar  name  conferred  on  them  by  Casimir  Funk)  vitamines. 
As  you  are  doubtless  aware,  the  chemical  nature  of  these  sub- 
stances is  as  yet  unknown.  Their  properties  cannot  therefore 
at  the  moment  be  used  to  illustrate  further  my  theme  concerning 
the  importance  of  molecular  structure  in  nutritional  phenomena, 
though  I  doubt  not  that  once  they  are  isolated  the  biochemist 
will  have  an  interesting  task  in  relating  their  action  to  their 
structure.  But  there  are  other  reasons  why  I  should  speak  to 
you  concerning  them.  I  have  received  credit — perhaps  too 
much  credit — as  pioneer  in  their  discovery.  Ten  years  ago  the 
time  was  ripe  for  the  emergence  of  certain  facts.  They  were  in 
the  air;  and  when,  in  the  progress  of  science,  this  is  the  case, 
questions  of  priority  lose  their  importance.  I  will  however 
relate  my  own.  experiences. 

During  1906  I  was  engaged  in  feeding  animals  upon  mixtures 
of  different  amino  acids,  and  of  necessity  had  to  employ  syn- 
thetic foods.  Starch,  fats,  and  salts  were  added  to  the  amino 
acids  to  complete  the  dietary.  The  first  circumstance  which 
set  me  thinking  was  the  observation  that  animals  prospered 
better  when  they  were  fed  upon  amino  acids  obtained  by  fully 
digesting  tissues  than  when  the  source  of  amino  acids  was  a 
separated  and  purified  protein  digested  in  the  same  way.  Lean 
beef,  for  instance,  gave  better  results  than  casein.  At  first 
one  was  inclined  to  attribute  the  differences  either  to  the  fact 
that  the  amino  acid  balance  was  better  in  the  former,  or  to  the 
presence  in  the  tissues  of  familiar  substances,  such  as  lecithin, 
but  I  could  not  get  confirmatory  evidence  for  this  supposition. 
The  first  strong  suggestion  that  something  special  had  to  be  looked 
for  came  not  from  my  main  experiments,  but  from  their  controls. 
In  the  latter  the  animals  were,  for  the  sake  of  comparison, 
given  intact  casein  instead  of  the  amino-acid  mixture,  the 
rest  of  the  diet  being  the  same.  Now,  for  a  long  time  these 
control  animals  grew  very  well  and  kept  in  good  health.  If 
growth  was  slow  I  put  it  down  to  the  fact  that  a  synthetic  diet 
might  in  any  case  be  somewhat  unsuitable  for  an  animal.  From 

(14) 


a  certain  date  onward,  however,  all  the  animals  on  casein  began 
to  do  badly.  They  showed  no  growth  at  all  and  their  health 
failed.  After  some  time  the  reason  occurred  to  me.  For  the 
preparation  of  amino  acids  I  used  pure  casein,  but  for  the  food 
of  the  control  animals  a  commercial  article  was  used.  On  the 
date  referred  to  I  had  begun  to  feed  these  animals  on  a  casein  prep- 
aration different  from  that  which  for  a  long  time  previous  had 
served  as  the  protein  supply  of  my  laboratory.  The  new  prep- 
aration had  just  come  on  the  market  and  in  appearance  seemed 
a  much  better  article;  but  there  was  soon  no  doubt  that  its  use 
was  the  cause  of  the  failures.  When  put  upon  the  old  casein 
supply  all  the  animals  grew  again! 

At  first  I  was  naturally  inclined  to  think  that  the  new  pro- 
tein had  suffered  some  sort  of  denaturation  during  the  course 
of  its  manufacture,  but  that  supposition  suffered  easy  disproof. 
When,  earlier,  I  began  experiments  with  synthetic  diets  I  added 
small  quantities  of  meat  extracts  and  extracts  from  yeast  to 
give  flavor  to  the  tasteless  food.  I  was  thinking  then  of  the 
animal's  "appetite,"  as  was  natural,  and  as  most  people  do  when 
they  start  such  experiments.  I  quickly  found,  however,  that 
rats  ate  synthetic  diets  very  well  without  such  additions,  and 
at  the  time  of  the  experience  with  casein  just  mentioned  I  had 
ceased  to  use  them.  Nevertheless  my  memory  at  this  time,  if 
not  my  notebooks,  carried  suggestions  concerning  the  influence 
of  the  extracts  which  led  me  to  try  adding  them  to  diets  con- 
taining the  new  casein,  with  striking  results.  Growth  was  now 
as  good,  and  sometimes  better  than  with  the  old  casein,  and 
growth  occurred,  too,  in  animals  which  were  eating  no  more,  or  even 
less,  than  other  individuals  living  on  the  pure  casern  diet  with- 
out addition  and  showing  continuous  loss  of  weight  as  a  result. 
The  extracts  powerfully  affected  nutrition.  I  now  extracted 
the  old  casein  with  various  solvents  and  finally  got  a  product 
which  behaved  exactly  like  the  new.  When  the  substances 
dissolved  out  were  returned  to  the  food,  growth  occurred  as 
before. l  I  wasted  next  a  good  deal  of  time  by  trying  the  effect 
of  various  familiar  substances  of  determined  nature  known  to  be 
in  yeast;  always  with  unsatisfactory  results. 

By  this  time  I  had  come  to  the  conclusion  that  there  must  be 
something  in  normal  foods  which  was  not  represented  in  a  syn- 
thetic diet  made  up  of  pure  protein,  pure  carbohydrate,  fats, 
and  salts;  and  something  the  nature  of  which  was  unknown. 
Yet  at  first  it  seemed  so  unlikely!  So  much  careful  scientific 
work  upon  nutrition  had  been  carried  on  for  half  a  century  and 
more — how  could  fundamentals  have  been  missed?  But, 
after  a  time,  one  said  to  oneself,  "Why  not?"  The  results  of 
all  the  classical  experiments  had  been  expressed  in  terms  of  the 
known  fundamental  foodstuffs:  but  these  had  never  been  ad- 

i  It  is  remarkable  what  a  considerable  proportion  of  the  vitamines 
present  in  milk  is  adsorbed  by  precipitated  casein.  A  failure  to  recognize 
this  has  often  obscured  the  results  of  feeding  trials. 

(15) 


ministered  pure!  If,  moreover,  the  unknown,  although  clearly 
of  great  importance,  must  be  present  in  very  small  amounts — 
again,  why  not?  Almost  infinitesimal  amounts  of  material 
may  have  a  profound  effect  upon  the  body,  as  pharmacology  and 
the  facts  concerning  immunity  assure  us.  Why  not  then  in 
nutritional  phenomena?  The  animal  depends  ultimately  upon 
the  plant  for  the  synthesis  of  materials  which  bulk  largely  in  its 
food:  there  is  no  reason  why  it  should  not  be  adjusted  so  as  to 
be  in  equal  need  of  substances  which  the  plant  makes  in  small 
amount.  Only  if  energy  were  the  sole  criterion  of  an  animal's 
needs  would  this  be  impossible;  but  certainly  it  is  not  the  sole 
criterion. 

So  my  faith  grew  in  the  existence  of  a  previously  unrecognized 
type  of  nutrient. 

At  this  period  I  spent  much  time  in  the  endeavor  to  isolate 
from  yeast  extracts  an  active  substance  with  definite  chemical 
properties,  but  wholly  without  success. 

The  experimental  period  that  I  have  been  describing  was, 
for  me,  in  one  particular,  unfortunate.  I  experienced  periods 
of  continuous  success  in  maintaining  growing  animals  upon  puri- 
fied dietaries  after  the  addition  of  very  small  quantities  of 
fractionated  yeast  preparations,  but  they  were  interspersed  with 
occasional  failures  which  shook  my  confidence.  Only  when 
milk,  in  small  amounts,  formed  the  addendum  did  failure  never 
follow.  The  explanation  is  now  clear.  The  protein  and  car- 
bohydrate used  in  my  experiments  were  thoroughly  purified 
and  standardized,  but  for  fat  I  used  lard.  But  lard,  as  many 
experimentalists  now  know  to  their  cost,  is  a  variable  fat.  What 
I  was  adding  or  witholding  in  my  early  experiments  was  vitamine 
B  alone.  I  taught  myself  nothing  about  vitamine  A,  which  is 
associated  with  most  animal  fats.  The  amount  of  it  in  com- 
mercial lard  varies  greatly;  and  I  have  no  doubt  that  when 
my  animals  did  well  the  lard  they  consumed  contained  enough 
of  it;  while  when  they  did  ill  the  lard  was  deficient  in  this 
particular. 

I  was  on  safer  ground  in  using  milk,  for  though  milk  is  not 
especially  rich  in  vitamines  it  always  contains  both  A  and  B. 
When,  therefore,  at  last,  I  ventured  on  publication  it  was  mainly 
ray  experiments  with  milk  that  I  described  in  proof  of  the 
existence  of  accessory  food  factors. 

A  great  step  forward  was  made  in  1913  when  McCollum  and 
Davis  made  it  clear  that  there  are  at  least  two  vitamines— those 
just  mentioned — concerned  in  nutrition;  for  we  have  since 
learned  how  great  is  the  nutritive  importance  of  fat-soluble  A, 
of-  which  the  existence  was  then  demonstrated.  It  seems  to 
me  fair  to  say  that  a  recognition  of  the  importance  of  a  factor 
associated  with  fats  was  implicit  if  not  explicit  in  papers  pub- 
lished at  this  time  by  Osborne  and  Mendel,  and  their  experi- 
ments in  proof  of  this  appeared  close  on  the  heels  of  McCollum's 
now  classic  publication.  Such  fundamental  matters  could  not 

(16) 


ndeed  long  escape  the  organized  and  intensive  work  which  was 
being  done  at  the  American  centers  of  activity. 

I  have  given  you  a  brief  account  of  my  own  early  experiences 
in  this  domain  (never  having  told  about  them  before)  because  I 
was  assured  that  you  would  care  to  hear  it.  I  fear  you  may  have 
found  it  trivial,  though  the  period  it  deals  with  contained  some 
thrilling  moments  for  me. 

It  would  have  been  more  useful,  I  imagine,  if  I  had  attempted 
to  give  you  a  critical  appraisement  of  the  present  position  of 
our  knowledge  of  vitamines.  To  attempt  one  now  would  be 
unwise,  for  to  be  of  use  it  would  take  much  time.  Advances 
have  been  real  during  the  last  year  or  two,  but  chiefly  in  matters 
of  detail.  Perhaps  no  considerable  advance  can  now  occur  until 
a  vitamine  has  been  isolated  in  pure  form  and  its  constitution 
determined.  I  am  sure  that  this  will  be  no  very  distant  ac- 
complishment. 

If  indeed  there  be  any  in  this  audience  who  feel  skeptical 
with  regard  to  the  whole  question  of  vitamines  or  at  any  rate 
with  regard  to  their  practical  importance  (there  are  still 
some  skeptics  in  my  own  country!),  ^feel  that  I  am  qualified  to 
ask  them  to  reconsider  their  attitude.  Apart  from  the  many 
hundreds  of  experiments  I  have  made  myself,  I  have  seen  the 
work  which  is  being  done  upon  the  subject  at  some  of  the  chief 
centers  of  activity.  I  can  testify  to  the  care  and  effort  which 
is  being  put  into  the  study  at  the  Lister  Institute  and  at  Uni- 
versity College,  London.  I  have  recently  paid  illuminating 
visits  to  the  departments  of  Drs.  Osborne  and  Mendel  at  Yale, 
and  to  that  of  Dr.  B.  V.  McCollum  at  the  Johns  Hopkins  Uni- 
versity. In  each  and  all  of  these  centers  one  finds  thorough 
organization  and  a  properly  critical  atmosphere.  The  technic 
used  in  the  study  of  vitamines  has  now  been  developed  till, 
in  its  own  special  way,  it  is  exact  and  reliable.  All  concerned 
have  to  talk  and  write  under  the  disadvantage  which  arises 
from  the  fact  that  the  actual  nature  of  these  substances  remains 
unknown,  but  in  spite  of  this  a  great  amount  of  real  knowledge  of 
practical  value  is  being  accumulated. 

Between  the  experiments  on  animals  and  actual  human  ex- 
perience there  are,  as  you  know,  links  enough.  The  absence  of 
one  particular  vitamine  from  the  food  is  the  whole  and  sufficient 
reason  for  the  occurrence  of  human  scurvy,  the  absence  of  another 
forms  the  main  factor  in  the  etiology  of  a  second  disease,  beriberi, 
the  absence  of  a  third  plays  at  least  a  large  part  in  the  induction 
of  rickets.  But  if  extreme  deficiency  in  such  factors  results 
in  actual  disease,  who  shall  say  how  much  vague  ill  health  may 
follow  upon  relative  deficiency?  That  is  the  consideration 
which  gives  importance  to  this  newest  chapter  in  the  science  of 
nutrition. 

While  the  newer  knowledge  which  has  grown  up  on  the  lines 
that  I  have  briefly  and  incompletely  indicated  has  undoubtedly 
important  practical  bearings,  those  engaged  in  the  work  should 

(17) 


doubtless  use  caution  in  their  relations  with  the  public.  We 
should  keep  a  sense  of  proportion.  It  would  be  wrong,  for 
instance,  or  so  it  seems  to  me  (I  have  heard  the  contrary  opinion 
expressed)  so  to  exaggerate  the  importance  of  the  fat-soluble 
vitamine  as  to  teach  that  vegetable  fats  which  do  not  contain 
it  should  disappear  from  the  market.  Fat,  as  such,  is  after  all 
a  valuable  and  necessary  food  of  which  it  is  none  too  easy  to 
maintain  a  supply.  We  should  rather  show  how  such  fats  are 
to  be  supplemented  properly  whenever  they  form  a  consider* 
able  part  of  the  public  supply. 

Again,  although  there  can  be  no  doubt  that  the  fundamental 
phenomena  of  nutrition  are  the  same  in  all  mammals,  there  are 
specific  differences  which  we  should  not  forget  in  applying  our 
laboratory  results.  Deficiencies  are  felt  more  immediately  and 
directly  by  the  small  animals  on  which  so  many  of  our  experi- 
ments are  done  than  by  larger  species  with  slower  metabolism. 
We  may  consequently  tend  to  exaggerate  the  general  importance 
of  this  or  that  factor.  We  should  not,  I  fancy,  make  too  much  of 
the  "biological  value"  of  proteins  in  connection  with  human  nu- 
trition until  more  observations  have  been  made  upon  human 
subjects.  The  most  favorable  balance  of  amino  acids  may  be 
different  in  different  species;  though  as  a  matter  of  fact  the 
weight  of  evidence  is  against  this  possibility.  At  any  rate, 
we  must  remember  that  physiological  adjustments  may  be  made 
during  long  periods  of  use  and  custom  which  could  not  occur 
during  the  relatively  brief  duration  of  an  experiment.  In 
connection  with  the  part  that  food  deficiencies  may  play  in 
the  causation  of  human  diseases,  we  should  bear  in  mind 
that  a  clinical  condition  is  usually  more  complex  than  condi- 
tions observed  in  the  laboratory  as-  the  result  of  varying  a 
single  factor. 

Nevertheless,  as  I  have  already  said,  there  exist  many  links 
of  evidence  to  show  that  laboratory  results  are  fully  paralleled 
in  human  experience,  and  evidence  of  this  sort  tends  to  increase. 
There  is  at  any  rate  no  fear  of  exaggerating  the  importance  of 
the  newer  outlook  when  the  rearing  of  children  is  in  question. 
If  one  had  to  sum  up  in  a  sentence  what  constitutes  that  newer 
outlook,  I  would  say  that  it  is  a  fuller  recognition  of  the  fact  that 
quality  is  as  important  as  quantity  in  all  that  concerns  nutrition. 
But  "quality"  must  be  read  in  a  new  sense,  a  sense  sufficiently 
defined  by  the  facts  I  have  been  discussing. 

I  referred  earlier  to  the  literal  fact  that  human  calorimetry 
is  an  American  science.  It  seems  to  me  as  I  think  of  those  who 
are  engaged  in  the  study  of  nutrition  on  the  fresh  and  extended 
lines  that,  unless  we  who  work  elsewhere  work  very  hard,  the 
new  science  which  is  developing  will  come  into  the  same  category. 


(18) 


Presentation  of  Chandler  Medal 

By  George  B.  Pegram 

COLUMBIA  UNIVERSITY,  NEW  YORK,  N.  Y. 

There  are  certain  names  that  stand  for  whole  periods  in  the 
existence  of  institutions,  epitomize  epochs  of  development  and 
accomplishment.  No  such  name  at  Columbia  stands  for  more 
than  Chandler.  Reaching  from  the  foundation  of  the  School  of 
Mines  in  1864  to  the  present  and  covering  nearly  half  a  century 
of  labor  and  responsibility  in  active  connection  with  the  develop- 
ment and  progress  of  scientific  work  at  Columbia,  his  great  per- 
sonality has  built  itself  into  the  structure  of  this  University 
in  so  intimate  a  fashion  that  the  keenest  analysis  could  not 
separate  it  out.  It  was,  therefore,  a  most  appropriate  action 
for  a  group  of  his  friends  to  present  to  the  Trustees  of  Columbia 
University  a  sum  of  money  constituting  the  Charles  Frederick 
Chandler  Foundation,  the  income  from  which  is  to  be  used  to 
provide  each  year  a  lecture  by  an  eminent  chemist  and  to 
provide  a  medal  to  be  presented  to  the  lecturer  in  public  recogni- 
tion of  his  achievements  in  science.  The  previous  lecturers  on  this 
Foundation  have  been  L.  H.  Baekeland,  Sc.D.,  W  F.  Hille- 
brand,  Ph.D.,  and  W.  R.  Whitney,  Ph.D. 

On  the  recommendation  of  a  University  committee,  the 
Trustees  of  Columbia  University  have  awarded  the  Chandler 
Medal  for  this  year  to  Frederick  Gowland  Hopkins,  F.R.C.P., 
F.R.S.,  F.I.C.,  F.C.S.,  Fellow  of  Trinity  College,  Honorary 
Fellow  of  Emanuel  College,  Cambridge,  Member  of  the  Medical 
Research  Council,  and  of  the  Consultative  Council  to  the  Min- 
ister of  Health,  Professor  of  Biological  Chemistry,  Cambridge 
University. 

Professor  Hopkins,  this  medal  is  presented  to  you. in  public 
recognition  of  your  pioneer  and  valuable  researches  in  biochemis- 
try, particularly  in  connection  with  food  accessories,  such  as  vita- 
mines,  and  your  public  service  on  the  Medical  Research  Council 
and  the  Consultative  Council  to  the  Minister  of  Health. 


(19) 


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